CaMKII γ, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine

被引:89
|
作者
Gu, Ying [1 ,2 ,3 ]
Chen, Ting [1 ]
Meng, Zhipeng [3 ]
Gan, Yichao [1 ]
Xu, Xiaohua [1 ]
Lou, Guiyu [3 ]
Li, Hongzhi [4 ]
Gan, Xiaoxian [5 ]
Zhou, Hong [1 ]
Tang, Jinfen [1 ]
Xu, Genbo [1 ]
Huang, Liansheng [1 ]
Zhang, Xiaohong [1 ]
Fang, Yongming [2 ]
Wang, Kai [2 ]
Zheng, Shu [2 ]
Huang, Wendong [3 ]
Xu, Rongzhen [1 ,2 ]
机构
[1] China Natl Minist Educ, Dept Hematol, Key Lab Canc Prevent & Intervent, Hangzhou, Zhejiang, Peoples R China
[2] Zhejiang Univ, Inst Canc, Sch Med, Affiliated Hosp 2, Hangzhou 310009, Zhejiang, Peoples R China
[3] City Hope Natl Med Ctr, Beckman Res Inst, Div Gene Regulat & Drug Discovery, Duarte, CA 91010 USA
[4] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Med, Duarte, CA 91010 USA
[5] Zhejiang Acad Med Sci, Hangzhou, Zhejiang, Peoples R China
基金
中国国家自然科学基金;
关键词
CHRONIC MYELOID-LEUKEMIA; FACTOR-KAPPA-B; PROTEIN-KINASE-II; BCR-ABL; STEM-CELLS; ANTILEUKEMIA ACTIVITY; CALMODULIN; APOPTOSIS; INHIBITION; PATHWAY;
D O I
10.1182/blood-2012-06-434894
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Bcr-Abl tyrosine kinase inhibitors (TKIs) have been a remarkable success for the treatment of Ph+ chronic myeloid leukemia (CML). However, a significant proportion of patients treated with TKIs develop resistance because of leukemia stem cells (LSCs) and T315I mutant Bcr-Abl. Here we describe the unknown activity of the natural product berbamine that efficiently eradicates LSCs and T315I mutant Bcr-Abl clones. Unexpectedly, we identify CaMKII gamma as a specific and critical target of berbamine for its antileukemia activity. Berbamine specifically binds to the ATP-binding pocket of CaMKII gamma, inhibits its phosphorylation and triggers apoptosis of leukemia cells. More importantly, CaMKII gamma is highly activated in LSCs but not in normal hematopoietic stem cells and coactivates LSC-related beta-catenin and Stat3 signaling networks. The identification of CaMKII gamma as a specific target of berbamine and as a critical molecular switch regulating multiple LSC-related signaling pathways can explain the unique antileukemia activity of berbamine. These findings also suggest that berbamine may be the first ATP-competitive inhibitor of CaMKII gamma, and potentially, can serve as a new type of molecular targeted agent through inhibition of the CaMKII gamma activity for treatment of leukemia. (Blood. 2012;120(24):4829-4839)
引用
收藏
页码:4829 / 4839
页数:11
相关论文
共 50 条
  • [1] The critical and specific transcriptional regulator of the microenvironmental niche for hematopoietic stem and progenitor cells
    Omatsu, Yoshiki
    Nagasawa, Takashi
    CURRENT OPINION IN HEMATOLOGY, 2015, 22 (04) : 330 - 336
  • [2] Sociology of Normal Stem and Progenitor Cells in CML Niche
    Welner, Robert S.
    Amabile, Giovanni
    Bararia, Deepak
    Staber, Philipp B.
    Czibere, Akos G.
    Tenen, Daniel G.
    BLOOD, 2012, 120 (21)
  • [3] The retinoblastoma tumor suppressor is a critical intrinsic regulator for hematopoietic stem and progenitor cells under stress
    Daria, Deidre
    Filippi, Marie-Dominique
    Knudsen, Erik S.
    Faccio, Roberta
    Li, Zhixiong
    Kalfa, Theodosia
    Geiger, Hartmut
    BLOOD, 2008, 111 (04) : 1894 - 1902
  • [4] Ex Vivo Expansion of Hematopoietic Stem and Progenitor Cells Using a Natural Product, Garcinol
    Nishino, Taito
    Iwama, Atsushi
    BLOOD, 2010, 116 (21) : 505 - 506
  • [5] Natural Killer Cells Target Neural Stem/Progenitor Cells through NKG2D
    Phillips, L. K.
    Gould, E. A.
    Krams, S. M.
    Palmer, T. D.
    Martinez, O. M.
    TRANSPLANTATION, 2012, 94 (10) : 284 - 284
  • [6] OXIDATIVE STRESS IN CML STEM AND PROGENITOR CELLS CORRELATES WITH RESPONSE TO IMATINIB
    Garcia, Regina
    Del Castillo, Santiago
    Entrena, Laura
    Isabel Rossell, Ana
    Campos, Arturo
    Paz Queipo de LLano, Maria
    Ramirez, Gemma
    CYTOMETRY PART B-CLINICAL CYTOMETRY, 2010, 78B (06) : 444 - 444
  • [7] The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells
    Rothe, Katharina
    Lin, Hanyang
    Lin, Kevin B. L.
    Leung, Amy
    Wang, Hui Mi
    Malekesmaeili, Mehrnoush
    Brinkman, Ryan R.
    Forrest, Donna L.
    Gorski, Sharon M.
    Jiang, Xiaoyan
    BLOOD, 2014, 123 (23) : 3622 - 3634
  • [8] TIGECYCLINE MAY SELECTIVELY TARGET LEUKEMIC STEM CELLS IN CML
    Kuntz, E. M.
    Baquero, P.
    Michie, A. M.
    Dunn, K.
    Tardito, S.
    Holyoake, T. L.
    CANCER DISCOVERY, 2017, 7 (11) : 1212 - 1212
  • [9] A critical role of FADD in hematopoietic stem and progenitor cells
    Zhang, Jianke
    Rosenberg, Stephen
    FASEB JOURNAL, 2010, 24
  • [10] C/EBPβ Is a Critical Regulator of CML Stem Cell Differentiation and Exhaustion Induced By Interferon-α
    Yokota, Asumi
    Hirai, Hideyo
    Hayashi, Yoshihiro
    Sato, Ryuichi
    Adachi, Hiroko
    Sato, Fumiko
    Sato, Atsushi
    Tamura, Akihiro
    Iwasa, Masaki
    Fujishiro, Aya
    Shoji, Tsukimi
    Kashiwagi, Takahiro
    Kamio, Naoka
    Torikoshi, Yusuke
    Miura, Yasuo
    Nakano, Masakazu
    Tashiro, Kei
    Maekawa, Taira
    BLOOD, 2016, 128 (22)